Infantile Spasms is one of the catastrophic epilepsies of early childhood. The disorder commonly leads to life- long epilepsy and mental retardation. At this time, there is no treatment for this disorder that improves long- term outcome, although ACTH can suppress the spasms in 40-60% of affected children. The development of new therapies has been severely hampered by the lack of a relevant animal model. Studies proposed here are based on the creation of an animal model that reproduces this clinical syndrome. In this model, the neocortex of infant rats is locally infused with the sodium channel antagonist, tetrodotoxin (TTX), which results in a regionalized blockade of neuronal activity. Within 2 weeks, many of these rats display frequent spasms that consist of brief flexions or extensions of axial musculature, which closely resemble infantile spasms. As in children, these events often occur in clusters EEG abnormalities are virtually identical to those seen in children. During a spasm, there is typically a generalized high voltage slow wave, followed by a period of marked voltage attenuation (electrodecrement) with superimposed higher frequency activity. Using rapid digital sampling we also have recently discovered high frequency oscillations (80-200 Hz) beginning at spasm onset. During the interictal period a hypsarrhythmic pattern is observed, consisting of high amplitude slow waves intermixed with frequent multifocal spikes. In the studies proposed here long term video/EEG recordings from animals with this syndrome will be used to fully characterize the natural course of this seizure disorder. We will determine: 1) when the spasms first appear 2) how long they persist and 3) variations in seizures frequency and clustering from animal to animal and from time to time in a given animal. We will also test rats for impairments in learning and memory and assess the ability of ACTH to suppress spasms. Our short-term goal is to develop reliable outcome measures of drug efficacy and the most time efficient and cost effective protocols for future drug trials. Our long-range goal is to use this animal model to screen new therapies based on a growing understanding of the biological basis of this devastating seizure disorder. PUBLIC HEALTH RELEVANCE: Infantile Spasms is one of the most severe epilepsies of early childhood for which there is no satisfactory treatment. Using a newly developed animal model of this disorder we plan to fully characterize the spasms in these animals and test the effectiveness of ACTH in suppressing these seizures. Our goal is to develop research and analytical protocols that can be used to test new generations of rational drug therapies for this devastating neurological disorder. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.